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204824Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204824Orig1s000 MEDICAL REVIEW(S) M E M O R A N D U M Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research FROM: Martha Donoghue, Medical Review Officer, DOP2 THROUGH: Suzanne Demko, Team Leader, DOP2 THROUGH: Patricia Keegan, Division Director, DOP2 TO: File SUBJECT: Clinical Review of Study Proposal SUBMIT DATE: June 27, 2013 PRODUCT: Methotrexate injection, for subcutaneous use (Otrexup™) NDA: 204824 APPLICATION HOLDER: Antares Pharma, Inc. DATE: October 25, 2013 Background: On December 14, 2012 Antares Pharma submitted NDA 204824 for Otrexup (methotrexate injection for subcutaneous administration) under the provisions of 505b(2). The application referenced three listed products: NDA 8085 (methotrexate tablets, USP; Dava Pharmaceuticals, Inc.), NDA 11719 (methotrexate injection, USP; Hospira), and ANDA 40632 (methotrexate preservative-free injection; Bedford Laboratories). Approved labeling for these listed products is not in compliance with Physician Labeling Rule (PLR) requirements. Otrexup is a single-use, pre-filled autoinjector containing 10, 15, 20, or 25 mg of methotrexate. In the original NDA submission, Antares Pharma submitted data showing that subcutaneous administration of Otrexup resulted in equal or greater bioavailability compared to orally administered methotrexate tablets and systemic exposure that was bioequivalent to the approved injectable product administered by the subcutaneous or intramuscular routes. The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) requested input from the Division of Oncology Products 2 (DOP2) to assist in the creation of the package insert for Otrexup in PLR format. In particular, DPARP sought advice regarding potential inclusion of oncology indications in the Otrexup label for consistency with approved labeling of other methotrexate products, and how best to bring approved labeling up to date with current scientific knowledge and PLR requirements. Page 1 of 2 Reference ID: 3396672 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- MARTHA B DONOGHUE 10/25/2013 SUZANNE G DEMKO 10/28/2013 PATRICIA KEEGAN 10/28/2013 Reference ID: 3396672 MEDICAL OFFICER - MEMO TO FILE Date: September 26, 2013 Subject: Labeling issues for NDA 204824, Otrexup (methotrexate) for Injection From: Peter Starke, MD, Medical Officer, Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) Introduction This memo summarizes the decisions made with respect to major labeling and indication issues for the proposed Otrexup (methotrexate) auto-injector submitted by Antares Pharma, Inc. These issues arose during the review cycle while making edits to the proposed labeling for the product, and were addressed through consultation with the Divisions of Oncology Products 2 (DOP2) and Dermatology and Dental Products (DDDP), the SEALD labeling team, and with the CDER senior management. Background This 505(b)(2) new drug application references three applications for methotrexate: NDA 11-719 for Methotrexate Injection EQ 50 mg base/2mL from Hospira, ANDA 40-632 for Methotrexate Preservative-Free Injection from Bedford, and NDA 08-085 for Methotrexate Tablets from Dava Pharmaceuticals. NDA 11-719 and NDA 08-085 currently reside in the FDA oncology division (DOP2). The proposed Trade Name for the product is Otrexup, and the PDUFA date is October 14, 2013 (action date October 11, 2013). Background regarding the product is below, followed by a summary of the labeling and indication issues. Methotrexate is a folate analog metabolic inhibitor currently indicated for the treatment of neoplastic diseases, severe psoriasis, rheumatoid arthritis (RA), and polyarticular-course juvenile rheumatoid arthritis (JRA) now called polyarticular juvenile idiopathic arthritis (pJIA). The proposed product is a drug/device combination consisting of a single-use, prefilled auto- injector intended for subcutaneous (SC) administration. It will be supplied in doses of 10 to 25 mg in 5 mg increments (10, 15, 20 and 25 mg). Because it is intended as a convenience formulation for self or caregiver use in the home setting, the applicant’s proposed indications for this product are limited to RA, pJIA, and psoriasis, and do not include treatment of neoplastic diseases. The applicant also requested a new indication of moderate psoriasis, and this was considered by the Division of Dermatology and Dental Products (DDDP) and rejected (b) (4) . No clinical trials were performed to support the application. Support for approval is based on: 1. The Agency’s previous findings of the safety and effectiveness of methotrexate in patients with RA, polyarticular JRA (pJIA), and psoriasis. 2. Literature reviews that support the safety and efficacy of SC administration of methotrexate as an alternative to oral or IM administration of MTX for these conditions and for the age groups for which they are currently approved. The literature supports SC administration, with higher systemic exposure and improvements in efficacy when administered SC or IM Reference ID: 3379701 NDA 204824 • Labeling memo • Otrexup (methotrexate) for injection 2 compared with similar oral doses, particularly at doses above 15 mg. The safety review of the literature and of the studies provided to this application did not reveal any new safety signals that would require additional labeling beyond those already labeled in the reference products. 3. A BA study (and MTX-11-003) in adults that supports efficacy with SC administration in patients with RA and psoriasis because it showed equal or greater bioavailability of the proposed MTX auto-injector product administered SC when compared to systemic exposure with orally administered MTX tablets. 4. A BE study (MTX-10-001) in adults that showed bioequivalence of systemic exposure between this auto-injector product administered SC in either the abdomen or the thigh and the approved injectable product administered with a needle and syringe either by the SC or IM route. 5. The applicant also performed an actual use labeling study (MTX-11-002) and a labeling and human factors study (MTX-11-004) to support the labeling and use of the proposed product, demonstrating that patients and caregivers could be taught to successfully use the product. These studies were requested by our CDRH colleagues. Labeling Issues Background The labeling for methotrexate is very old, the listed originator oral and parenteral products having been approved in the 1950’s. There are multiple generic products. None of the labels are in PLR format, although they have been updated at some point with the DESI indications, and the PI for the parenteral formulation is unified in that it contains includes oral dosing information. This will be the first methotrexate product to use PLR formatting. The labeling contains a Boxed Warning for multiple toxic effects as well as multiple Warnings and Precautions. There are no clinical trials listed in the Clinical Trials section, although a scattering of clinical information may be found in multiple sections, including the Clinical Pharmacology, Adverse Events, and Pediatrics sections, as well as in the D&A section. The applicant wishes to update the labeling with some new clinical and other information and add clinical trials from the literature. However, this is not appropriate for a 505(b)(2) application for which the applicant is not the listed drug. The doses used in RA, pJIA, and psoriasis range from about 5 mg to 30 mg. For RA, the recommended starting dose is 7.5 mg administered orally as a single weekly dose. For pJIA the recommended starting dose is 10 mg/m2, and the route is not specified. For Psoriasis, the recommended starting dose is between 10 and 25 mg, administered orally, IM, or IV. For oncologic indications, doses range much higher (high-dose treatments, often with leucovorin rescue) and are administered IV and by other routes (intra-arterial, intrathecal). Adverse events noted with methotrexate use span the full range of doses and indications, making separation of adverse events, warnings, and warnings contained in the Boxed Warning difficult or impossible based on the indication. Nevertheless, it is clear that some of these warnings and other wording are directed at the oncology indications, creating difficulty in separating out the labeling that is specific for one indication from that for the others. Reference ID: 3379701 NDA 204824 - Otrexup (methotrexate) injection Information Request Draft 9/12/2013 We are providing the following initial labeling comments for your product. Additional comments, including comments about the Instructions for Use (IFU), trainer Instructions for Use (TIFU), and Patient Package Insert (PPI) will be forthcoming as our reviews progress. 1. We have made significant changes to the proposed Prescribing Information (PI) for your product. We recognize that Otrexup will be the first instance of Physicians Labeling Rule (PLR) labeling for a methotrexate product, and that you have proposed new language to deal with these changes. However, your product relies on listed drug labeling
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